Adenoviruses are widely used vectors for gene delivery because of their ability to transduce a wide range of dividing and nondividing cell types. Adenoviruses typically bind and enter cells through a process involving the interactions of the adenovirus fiber protein, which is thought to mediate cell binding via a Fiber receptor, the coxsackievirus-adenovirus receptor (CAR) that is expressed on mammalian cells. The use of adenoviral vectors as therapeutic agents has been hampered, in part, by broad viral tropism and diminished expression of CAR in many cancers. Genetic strategies to re-target viral infection to alternate receptors through modifications of capsid genes has also been impeded by the large viral genome and complex adenoviral gene organization, and the fact that capsid gene alterations often interfere with protein structure, viral packaging, and infection. Improved compositions and methods are required to screen genetic alterations in viral capsid proteins.